PMID- 27230587 OWN - NLM STAT- MEDLINE DCOM- 20170406 LR - 20170406 IS - 1532-8511 (Electronic) IS - 1052-3057 (Linking) VI - 25 IP - 8 DP - 2016 Aug TI - Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain. PG - 1997-2003 LID - S1052-3057(16)30010-6 [pii] LID - 10.1016/j.jstrokecerebrovasdis.2016.04.002 [doi] AB - BACKGROUND: Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain. METHODS: Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation. RESULTS: Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups. CONCLUSIONS: Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies. CI - Copyright (c) 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. FAU - Shang, Jingwei AU - Shang J AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Yamashita, Toru AU - Yamashita T AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Kono, Syoichiro AU - Kono S AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Morihara, Ryuta AU - Morihara R AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Nakano, Yumiko AU - Nakano Y AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Fukui, Yusuke AU - Fukui Y AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Li, Xianghong AU - Li X AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Hishikawa, Nozomi AU - Hishikawa N AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Ohta, Yasuyuki AU - Ohta Y AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. FAU - Abe, Koji AU - Abe K AD - Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address: shangjw2@gmail.com. LA - eng PT - Journal Article DEP - 20160524 PL - United States TA - J Stroke Cerebrovasc Dis JT - Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association JID - 9111633 RN - 0 (Anticoagulants) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Plant Lectins) RN - 0 (tomato lectin) RN - 5Q7ZVV76EI (Warfarin) RN - 9007-34-5 (Collagen) RN - 9NDF7JZ4M3 (Rivaroxaban) RN - EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor) RN - EC 3.4.22.- (Caspase 3) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Animals MH - Anticoagulants/*administration & dosage MH - Body Weight/drug effects MH - *Brain/drug effects/metabolism/pathology MH - Caspase 3/metabolism MH - Collagen/metabolism MH - Disease Models, Animal MH - Drug Administration Schedule MH - Gene Expression Regulation/*drug effects MH - Glial Fibrillary Acidic Protein/metabolism MH - Infarction, Middle Cerebral Artery/*prevention & control MH - Male MH - Matrix Metalloproteinase 9/metabolism MH - Plant Lectins/metabolism MH - Rats MH - Rats, Wistar MH - Receptors, Platelet-Derived Growth Factor/metabolism MH - Rivaroxaban/*administration & dosage MH - Warfarin/*administration & dosage OTO - NOTNLM OT - Ischemia OT - neurovascular unit dissociation OT - rivaroxaban OT - thrombolysis OT - warfarin EDAT- 2016/05/28 06:00 MHDA- 2017/04/07 06:00 CRDT- 2016/05/28 06:00 PHST- 2015/12/24 00:00 [received] PHST- 2016/03/20 00:00 [revised] PHST- 2016/04/01 00:00 [accepted] PHST- 2016/05/28 06:00 [entrez] PHST- 2016/05/28 06:00 [pubmed] PHST- 2017/04/07 06:00 [medline] AID - S1052-3057(16)30010-6 [pii] AID - 10.1016/j.jstrokecerebrovasdis.2016.04.002 [doi] PST - ppublish SO - J Stroke Cerebrovasc Dis. 2016 Aug;25(8):1997-2003. doi: 10.1016/j.jstrokecerebrovasdis.2016.04.002. Epub 2016 May 24.